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Regulatory Roles of Histamine in Pre-Eclampsia

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Regulatory Roles of Histamine in Pre-Eclampsia Placental Genomics: Regulatory Roles of Histamine in Pre-eclampsia Obed Brew A commentary submitted in partial fulfilment of the requirements of University of West London for the degree of Doctor of Philosophy 2017 2 Acknowledgements My sincere thanks to Dr Mark Sullivan and Professor Anthony Woodman for their dedicated and continual support for this work. My sincere thanks also to my family for their patience and endurance. Acts 20:24 3 Abstract Aim: Pre-eclampsia (PE) is a multifactorial pregnancy related disorder and a major cause of perinatal mortality. Mothers who develop PE present with clinical symptoms akin to experimentally induced elevated histamine. Maternal blood histamine is elevated, while Diamine Amine Oxidase (DAO) level is diminished in PE. The abnormalities in placental development and functions linked to aetiology of PE have similarities with effects of elevated histamine in other tissues, yet the effects of the elevated histamine on placental function were not directly investigated. Therefore, a series of studies were undertaken and published to increase our knowledge and elucidate our understanding on: (1) the functionality of elevated histamine in the placenta; (2) the causes of the elevated histamine in PE placentae, and (3) of the effects of the elevated histamine on placental gene expression and the implications for PE. Methods: A series of published high-throughput methodologies have been critically discussed in this commentary. Molecular biotechnology and bioinformatics methodologies such as, ex vivo elevated histamine placental explant model, gene cloning, RT-qPCR, In situ hybridization, microarrays, enzymological analysis, ELISA, Immunohistochemistry, RNA expression array assay analysis, integrated meta-gene analyses, Gene Set Enrichment Analysis, Gene Ontology and biological pathway analyses, Leading Edge Metagene analysis, Systematic Reviews with Meta- analysis and Causal effect analysis have been discussed. The rationale for the appropriate use of these methods to investigate the topological expression of placental histamine receptors, regulation of histamine synthesis and production, the effects of elevated histamine on gene expression, and functional roles of the elevated histamine regulated genes in human placenta is also critically discussed. Results: The findings show that defective Histamine-DAO-Axis (dHDA) underpins PE, and this defect may be precipitated in early pregnancy, thus predating the onset of the clinical manifestation of PE in mothers who later develop the complication; histamine receptors H1 and H2, and DAO messages are expressed in juxtapositions at the foeto-maternal interface, Histidine Decarboxylase (HDC) HDC activity is elevated in PE placentae; and while elevated histamine up- regulates the proteins for Th1-like cytokines, it also down-regulates DAO message expression after prolonged exposure in the placenta. The findings further show that lipopolysaccharides and pro-inflammatory cytokines including IL-10 and INF- increase histamine production in the placenta; and the histamine has a positive feedback loop regulatory relation with the pro- inflammatory cytokines. Furthermore, the validation of Elevated Histamine Model (EHM), an in vitro model designed for studying histamine effect in placenta showed that placental micro explants (∼50 mg) in long-term culture (explants that have undergone syncytiotrophoblast regeneration) at the liquid-gas interface in 8% oxygen is an optimum culture condition to study effects of histamine in the placenta. EHM produced RNA with quality akin to time zero pre-culture explants. The works also led to the identifications of a core set of significant genes that are consistently expressed in both normal (NP) in PE placentae but at varying levels, and a further subset of significant genes expressed consistently only in PE placentae (PE specific genes). Comparison of EHM significant genes with the PE specific genes confirmed the presence of 270 consistently expressed genes that appear to underpin the effects of elevated histamine in the placenta with implications for PE pathogenesis. Further analyses of these EHM genes in PE placentae showed that the natural process by which pre-eclampsia develops is affected by the amount of histamine in the maternal blood and placenta, and the natural process by which pre-eclampsia develops is indirectly affected by histamine via covariate functional groups regulated by specific histamine regulated PE placental genes. 4 Conclusion: Histamine receptor genes are expressed at the foeto-maternal interface; DAO genes are expressed in the placenta; HDC activity levels are increased in PE placentae; there is cross-talk between histamine, DAO and cytokines in the placenta; elevated histamine regulated the expression of specific genes in the placenta and these genes are abnormally expressed in PE placentae; the functions of the histamine regulated genes also identified in PE placentae are involved in tissue morphology and possibly poor placentation, metabolic defects, endothelial dysfunction, inflammation, immunologic response, angiogenic and anti-angiogenic response in PE placentae. Therefore it is reasonable to conclude that the elevated histamine observed in PE would have pathophysiological roles in PE and early detection leading to effective control of maternal blood histamine levels has survival values and it’s thus recommended. 5 Table of Contents Contents Abstract ......................................................................................................................................................................... 4 Table of Figures ............................................................................................................................................................ 9 List of Tables ................................................................................................................................................................ 9 List of Abbreviations ................................................................................................................................................. 10 Chapter 1 ..................................................................................................................................................................... 12 Introduction ................................................................................................................................................................. 12 1.1 Background ....................................................................................................................................................... 12 1.2 Theories of Pre-eclampsia Pathophysiology and the Role of Histamine .......................................................... 14 1.3 How could Histamine be the missing link in Pre-eclampsia Pathogenesis? ..................................................... 16 1.4 Academic Biography ........................................................................................................................................ 21 1.5 Portfolio of Publications ................................................................................................................................... 23 1.6 Themes for Commentary .................................................................................................................................. 25 Chapter 2 Theme 1: Histamine links with Pre-eclampsia: Evidence from Systematic Reviews ................................. 26 2.1 Introduction ....................................................................................................................................................... 27 Account of originality at the time of publication .................................................................................................... 27 2.2 Contributions made by the reviews to the understanding of the impact of Maternal Blood Histamine on pre- eclamptic pregnancy outcome................................................................................................................................. 28 2.2.1 The Roles of Pre-formed and De Novo Histamine in Pregnancy .............................................................. 28 2.2.2 The Sources of Histamine during Pregnancy ............................................................................................ 30 2.2.3 Histamine Metabolism in Pre-eclampsia ................................................................................................... 31 2.2.4 Association of diminished maternal DAO activity and increasing blood histamine with Pre-eclampsia .. 35 2.3 Conclusion ........................................................................................................................................................ 41 Chapter 3 Theme 2: Methodological Considerations- Model for studying ex vivo placental gene expression in response to histamine .................................................................................................................................................. 42 3.1 Introduction: ..................................................................................................................................................... 43 3.2 Sub-section (1): Contributions made to the knowledge and understanding of Patients, the Placenta and Tissue Culture (#2 - #11) ..................................................................................................................................................
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